A major concern with ischemic diseases, such as cardiovascular disease and diabetes, is the high risk associated with percutaneous intervention and the inability to target specific tissues. Ultrasound (US) and ultrasound contrast agents provide a way to non-invasively provide proangiogenic therapy. Though numerous studies demonstrate this ability, the exposure conditions, date at which angiogenesis is observed and uses of contrast agents all vary. The mechanism of ultrasound-induced angiogenesis is not well understood. The assumed process, for studies involving contrast agent, is inertial cavitation, however microbubbles can also cause microstreaming and liquid jets. Mechanisms for cases without contrast agent have not been well documented. A major impediment to progress in the field is this deficit in biophysical understanding apparent from the lack of unified exposure conditions. Therefore, the long term objective of this project is to understand the underlying biophysical processes that contribute to US-induced angiogenesis in an effort to design an optimal treatment course. The aims of this project are to examine the role of contrast agents and the ultrasonic exposure parameters. Specifically, to determine if ultrasound contrast agents are necessary for the angiogenic effects, and what role, if any, inertial cavitation plays. This will be determined by comparing the angiogenic response to the collapse thresholds of the contrast agent. After which, several factorial based studies will be used to assess the non- bubble related mechanisms (pulse duration, exposure duration, pulse repetition frequency) of the phenomena. Both capillary density and VEGF expression (via real time polymerase chain reaction) will be used to quantitatively measure angiogenesis. US-induced angiogenesis is an existing phenomenon that has been documented. In addition to being non-invasive, US-induced angiogenesis is also spatially and temporally specific, unlike the current methods of transmyocardial revascularization and experimental genetic or molecular models. Because of the potential to increase the therapeutic effectiveness and the number of patients eligible for proangiogenic therapy, this project seeks to explain the biophysical mechanisms involved in the ultrasound-induced angiogenesis.